Cancer represents the phenotypic end-point of multiple genetic lesions that endow cells with a full range of biological properties required for tumorigenesis. Indeed, a hallmark genomic feature of many cancers, including, for example, B cell cancer, lung cancer, breast cancer, ovarian cancer, pancreatic cancer, and colon cancer, is the presence of numerous complex chromosome structural aberrations—including non-reciprocal translocations, amplifications and deletions.
Karyotype analyses (Johansson, B., et al. (1992) Cancer 69, 1674-81; Bardi, G., et al. (1993) Br J Cancer 67, 1106-12; Griffin, C. A., et al. (1994) Genes Chromosomes Cancer 9, 93-100; Griffin, C. A., et al. (1995) Cancer Res 55, 2394-9; Gorunova, L., et al. (1995) Genes Chromosomes Cancer 14, 259-66; Gorunova, L., et al. (1998) Genes Chromosomes Cancer 23, 81-99), chromosomal CGH and array CGH (Wolf M et al. (2004) Neoplasia 6(3)240; Kimura Y, et al. (2004) Mod. Pathol. 21 May (epub); Pinkel, et al. (1998) Nature Genetics 20:211; Solinas-Toldo, S., et al. (1996) Cancer Res 56, 3803-7; Mahlamaki, E. H., et al. (1997) Genes Chromosomes Cancer 20, 383-91; Mahlamaki, E. H., et al. (2002) Genes Chromosomes Cancer 35, 353-8; Fukushige, S., et al. (1997) Genes Chromosomes Cancer 19:161-9; Curtis, L. J., et al. (1998) Genomics 53, 42-55; Ghadimi, B. M., et al. (1999) Am J Pathol 154, 525-36; Armengol, G., et al. (2000) Cancer Genet Cytogenet 116, 133-41), fluorescence in situ hybridization (FISH) analysis (Nilsson M et al. (2004) Int J Cancer 109(3):363-9; Kawasaki K et al. (2003) Int J Mol. Med. 12(5):727-31) and loss of heterozygosity (LOH) mapping (Wang Z C et al. (2004) Cancer Res 64(1):64-71; Seymour, A. B., et al. (1994) Cancer Res 54, 2761-4; Hahn, S. A., et al. (1995) Cancer Res 55, 4670-5; Kimura, M., et al. (1996) Genes Chromosomes Cancer 17, 88-93) have identified recurrent regions of copy number change or allelic loss in various cancers.
Multiple Myeloma (MM) is characterized by clonal proliferation of abnormal plasma cells in the bone marrow, usually with elevated serum and urine monoclonal paraprotein levels and associated end-organ sequelae. MM accounts for more than 10% of all hematological malignancies and is the second most frequent hematological cancer in the US after non-Hodgkin lymphoma. MM is typically preceded by an age-progressive condition termed Monoclonal Gammopathy of Undetermined Significance (MGUS), a condition present in 1% of adults over age of 25 that progresses to malignant MM at a rate of 0.5-3% per year (Kyle, R. A., and Rajkumar, S. V. (2004) N Engl J Med 351, 1860-1873; Mitsiades et al. (2004) Cancer Cell 6, 439-444; Bergsagel et al. (2005) Blood 106, 296-303). MM remains incurable despite high-dose chemotherapy with stem cell support. Novel agents such as thalidomide, the immunoregulator Revlimid, and the proteasome inhibitor bortezomid can achieve responses in patients with relapsed and refractory MM, however, the median survival remains at 6 years with only 10% of the patients surviving at 10 years (Barlogie et al. (2004) Blood 103, 20-32; Richardson et al. (2005) Best Pract Res Clin Haematol 18, 619-634; Rajkumar, S. V., and Kyle, R. A. (2005) Mayo Clin Proc 80, 1371-1382).
Significant effort has been directed towards the identification of the molecular genetic events leading to this malignancy with the goals of improving early detection and providing new therapeutic targets. Unlike most hematological malignancies and more similar to solid tissue neoplasms, MM genomes are typified by numerous structural and numerical chromosomal aberrations (Kuehl, W. M., and Bergsagel, P. L. (2002) Nat Rev Cancer 2, 175-187). Reflecting the increasing genomic instability that characterizes disease progression, metaphase chromosomal abnormalities can be detected in only one-third of newly diagnosed patients but are evident in the majority of patients with end-stage disease (Fonseca et al. (2004) Cancer Res 64, 1546-1558). Yet, applying DNA content or interphase fluorescence in situ hybridization (FISH) analyses, aneuploidy and translocations are detectable in virtually all subjects with MM and even MGUS (Chng et al. (2005) Blood 106, 2156-2161; Bergsagel, P. L., and Kuehl, W. M. (2001) Oncogene 20, 5611-5622). Extensive molecular (Kuehl, W. M., and Bergsagel, P. L. (2002) Nat Rev Cancer 2, 175-187; Shaughnessy, J. D., Jr., and Barlogie, B. (2003) Immunol Rev 194, 140-163), cytogenetic (Bergsagel, P. L., and Kuehl, W. M. (2001) Oncogene 20, 5611-5622; Sawyer et al. (1998) Blood 92, 4269-4278; Debes-Marun et al., (2003) Leukemia 17, 427-436), chromosomal CGH (Avet-Loiseau et al. (1997) Genes Chromosomes Cancer 19, 124-133; Cigudosa et al. (1998) Blood 91, 3007-3010), analyses have uncovered a number of recurrent genetic alterations in MM and its precursor MGUS, some of which have been linked to disease pathogenesis and clinical behavior.
Chromosomal translocations involving the IgH locus at 14q32 and various partner loci are seen in most MM cell lines, consistent with MM's origin from antigen-driven B cells in post-germinal centers (Kuehl, W. M., and Bergsagel, P. L. (2002) Nat Rev Cancer 2, 175-187). Five recurrent loci/genes are commonly juxtaposed to the powerful IG enhancer locus elements, including 11q13 (CCND1), 4p 16 (FGFR3/WHSC1), 6p21 (CCND3), 16q23 (MAF) and 20q11 (MAFB), resulting in deregulated expression of these target genes in neoplastic plasma cells (Bergsagel, P. L., and Kuehl, W. M. (2005) J Clin Oncol 23, 6333-6338). Such translocations, present in MGUS, are considered central to the genesis of MM, whereas disease progression is associated with mutational activation of NRAS or KRAS oncogenes and inactivation of CDKN2A, CDKN2C, CDKN1B and/or PTEN tumor suppressor genes. Late mutational events involve inactivation of TP53 and secondary translocations that activate MYC (Kuehl, W. M., and Bergsagel, P. L. (2002) Nat Rev Cancer 2, 175-187).
Two oncogenic pathways have been hypothesized for the pathogenesis of MGUS/MM. Hyperdiploid MM involves multiple trisomies of chromosomes 3, 5, 7, 9, 11, 15, 19, and 21, whereas the non-hyperdiploid pathway is associated with a prevalence of IgH translocations (Bergsagel et al. (2005) Blood 106, 296-303; Fonseca et al. (2004) Cancer Res 64, 1546-1558; Cremer et al. (2005) Genes Chromosomes Cancer 44, 194-203). Ploidy level also impacts prognosis: non-hyperdiploidy imparts short survival (Fonseca et al. (2004) Cancer Res 64, 1546-1558) that can be counteracted by the presence of trisomies involving chromosomes 6, 9, 11, and 17. Complete or partial deletion of chromosome 13, especially band 13q14, is commonly observed in non-hyperdiploid MM and confers high risk (Fonseca et al. (2004) Cancer Res 64, 1546-1558). Employing gene expression profiling, there have been efforts in trying to define molecular subgroups of MM with clinical correlates and a novel TC classification (translocation/cyclin D) of MM has been proposed (Bergsagel et al. (2005) Blood 106, 296-303). A recent analysis of gene expression profiles of 511 outcome-annotated MM cases has pointed to amplification at 1q21 as an independent predictor of outcome. While these antecedent efforts have led to important insights into the pathogenesis and clinical behavior of MM, the presence of so many recurrent genomic alterations points to the existence of many undefined genetic elements which may prove relevant to disease initiation, progression and maintenance, as well as drug responsiveness. Specifically, while recurrent chromosomal gains have been mapped to 1q, 3q, 9q, 11q, 12q, 15q, 17q, and 22q and recurrent losses to 6q, 13q, 16q, Xp, and Xq, the presumed cancer-relevant targets in these loci are not yet known. Thus, the discovery of these new myeloma-relevant genes is likely to provide improved classification systems that will guide clinical management and identify new oncogenes and therapeutic targets.